Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characterized by elevated serum autoantibody levels and tissue pathology involving kidney, skin, joints, brain, lung and heart. The predominant autoantigens in SLE are the components of nucleosomes (DNA, histones) and small nuclear ribonucleoprotein particles (Sm, nRNP-A and nRNP-C). The high levels of circulating antibodies induce immune complex deposits in tissues where subsequent complement activation leads to inflammation. Therapies to manage SLE have been limited to drugs that suppress immune function or drugs that control end-organ inflammation.
The mechanisms underlying the breakdown in tolerance associated with SLE remain poorly defined. The presence of polyclonal activators and deficiencies in B cell tolerance mechanisms may both play roles in the production of autoantibodies. Viral infection and microbial agents act as polyclonal B cell activators upon ligation of Toll like receptors (TLRs). Similarly, apoptotic cells have been linked to the autoreactive response of SLE and may also mediate innate immune activation through TLR 9. Binding of polyclonal activators to TLRs may synergize with signals transduced through the BCR to induce B cell activation and differentiation to antibody secreting cells. For example, ligands for TLR2/6, TLR3, TLR4, TLR5, TLR7 and TLR9 have been identified on uncleared apoptotic cells or as products of bacterial or viral infections. Stimulation through these receptors coupled with ligation of antigen-specific BCR may provide sufficient costimulation to drive immune activation.
Several mechanisms that maintain autoreactive B cells in an unresponsive state have been identified using immunoglobulin transgenic mice. The first mechanism induces a functionally inactive state termed anergy. In this model, B cells from hen egg lysozyme-specific immunoglobulin transgenic mice (anti-HEL) develop in the presence of soluble hen egg lysozyme (sHEL). Peripheral B cells from these mice exhibit an unresponsive phenotype characterized by an inability to renew signal transduction upon BCR ligation with self-antigen. These cells exhibit downmodulated surface B cell receptor (BCR), an inability to secrete antibody in response to stimulation with lipopolysaccharide (LPS) and anti-IgM, a shortened half-life and an inability to compete with naïve B cells for follicular niches. Mechanistically, the sustained extracellular response kinase (ERK) activation exhibited by anti-HEL specific B cells acts to inhibit TLR 9-induced plasma cell differentiation.
Another mechanism of tolerance has been described that regulates B cells specific for dsDNA. Immunoglobulin transgenic (IgTg) B cells expressing a BCR specific for dsDNA exhibit a phenotype similar to the anti-HEL B cells. Unlike anti-HEL B cells, anti-dsDNA B cells become activated to secrete autoantibodies upon engagement by activated TH cells. However, if the T cell help becomes available in the presence of CD4+CD25+ T regulatory (Treg) cells, the anti-dsDNA specific B cells fail to develop into autoantibody secreting cells. These data define an indirect role for regulatory T cells in maintaining autospecific B cells in an unresponsive state (Seo and Erickson, (2002) Immunity 16:535).
It has previously been reported that B cells specific for lupus-associated Smith antigen (Sm) remain unresponsive by a mechanism involving peripheral anergy. These mice carry a 2-12 immunoglobulin heavy chain transgene paired with a Vk8 light chain transgene encoding a low affinity Sm-specific BCR. 2-12/Vk8 B cells exhibit a mature phenotype, but respond suboptimally to LPS and anti-IgM signaling indicating an anergic phenotype. Unlike the anti-HEL B cells, 2-12/Vk8 cells enter the follicle normally and have a normal life span. In addition, these cells fail to downregulate surface Ig and respond to CD40L and IL-4 suggesting that anergy to Sm can be overcome by T cell co-stimulation.
There is a need in the art for compositions and methods for maintaining and/or rendering autoreactive B cells unresponsive.